The Associations of Single Nucleotide Polymorphisms in miR-146a, miR-196a and miR-499 with Breast Cancer Susceptibility

G The Associations of Single Nucleotide Polymorphisms in miR-146a, miR-196a and miR-499 with Breast Cancer Susceptibility Ping-Yu Wang 0 Zong-Hua Gao 0 Zhong-Hua Jiang 0 Xin-Xin Li 0 Bao-Fa Jiang 0 Shu-Yang Xie 0 Balraj Mittal, Sanjay Gandhi Medical Institute, India 0 1 Department of Epidemiology, Binzhou Medical University , YanTai, ShanDong , P.R. China , 2 Department of Epidemiology, School of Public Health, Shandong University , JiNan, ShanDong , P.R. China , 3 Department of Imaging, Yantai Traditional Chinese Medical Science Hospital , YanTai, ShanDong , P.R. China Background: Previous studies have investigated the association between single nucleotide polymorphisms (SNPs) located in microRNAs (miRNAs) and breast cancer susceptibility; however, because of their limited statistical power, many discrepancies are revealed in these studies. The meta-analysis presented here aimed to identify and characterize the roles of miRNA SNPs in breast cancer risk, and evaluate the associations of polymorphisms in miR-146a rs2910164, miR-196a rs11614913 and miR-499 rs3746444 with breast cancer susceptibility, respectively. Methodology/Principal Findings: The PubMed and Embases databases were searched updated to 31st December, 2012. The complete data of polymorphisms in miR-146a rs2910164, miR-196a rs11614913 and miR-499 rs3746444 from casecontrol studies for breast cancer were analyzed by odds ratios (ORs) with 95% confidence intervals (CIs) to reveal the associations of SNPs in miRNAs with breast cancer susceptibility. Totally, six studies for rs2910164 in miR-146a, involving 4225 cases and 4469 controls; eight studies for rs11614913 in miR-196a, involving 4110 cases and 5100 controls; and three studies of rs3746444 in miR-499, involving 2588 cases and 3260 controls, were investigated in the meta-analysis. The rs11614913 (TT+CT) genotype of miR-196a2 was revealed to be associated with a decreased breast cancer susceptibility compared with the CC genotypes (OR = 0.906, 95% CI: 0.825-0.995, P = 0.039); however, no significant associations were observed between rs2910164 in miR-146a (or rs3746444 in miR-499) and breast cancer susceptibility. Conclusions: This meta-analysis demonstrates the compelling evidence that the rs11614913 CC genotype in miR-196a2 increases breast cancer risk, which provides useful information for the early diagnosis and prevention of breast cancer. - Funding: This study was partly supported by the Program for New Century Excellent Talents in University (NCET-10-0919), and National Natural Science Foundation of China (No. 81141114, 81200601). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. Competing Interests: The authors have declared that no competing interests exist. MicroRNAs (miRNAs) are non-coding RNA molecules that can act as tumor suppressor genes or oncogenes [1]. There are more than 1000 miRNA genes in the human genome [24], which regulate the translation or degradation of human messenger RNA (mRNA) by sequence complementarity [57]. MiRNAs regulate approximately 30% of human genes [8]. The genetic variants of a miRNA may affect its biogenesis and maturation [9,10], which are causally linked to the pathogenesis of numerous diseases, including cancer [11,12]. Several miRNA polymorphisms have been reported to affect miRNA processing or miRNA-mRNA interactions [12,13]. Single nucleotide polymorphisms (SNPs) in miRNAs can be used as genetic markers to predict breast cancer susceptibility or prognosis. For example, a significant association was identified between polymorphism rs11614913 in miR-196a2 and breast cancer risk [14]. Breast cancer patients with the variant C allele in miR-146a produced higher levels of mature miR-146, which may predispose women to an earlier age of onset of familial breast cancer [15,16]. The variant genotypes rs3746444 in miR-499 were also reported to be associated with significantly increased risks of breast cancer [17]. The rs6505162 with the CC genotype in miR-423 could reduce the risk of breast cancer development [18]. Nevertheless, some SNPs in miRNAs showed no association with breast cancer risk [19,20]. Catucci et al. reported that the SNPs rs11614913 in miR-196a2, rs3746444 in mir-499 and rs2910164 in miR-146a were not related to breast cancer risk [19]. Jedlinskis study also did not support the association of polymorphism rs11614913 in miR-196a2 with breast cancer susceptibility [20]. Thus, there are many discrepancies concerning the relationship between SNPs in miRNA (miR-146a, miR-196a2, and miR-499) and breast cancer susceptibility, which may be attributed to sample sizes, different ethnic group and different miRNAs studied. Meta-analysis is statistical methods for contrasting and combining results from different studies, in the hope of identifying sources of disagreement among those results [21]. A meta-analysis allows derivation and statistical testing of overall factors and effectsize parameters, which can identify whether a publication bias exists or whether the results are more varied than what is expected from the sample diversity. Though several meta-analysis studies evaluating the roles of miRNA gene polymorphisms in cancer have been published, few meta-analysis studies have assessed the associations of three SNPs of miR-146a, miR-196a and miR-499 with breast cancer susceptibility. Therefore, we selected these three SNPs in this meta-analysis, according to two basic principles as established in a previous study [22]: first, the minor allele frequency of the SNP was not less than 5%; Secondly, only functional SNPs were selected. This meta-analysis aimed to resolve the discrepancies among the results of the associations of these miRNAs (miR-146a, miR-196a2, and miR-499) with breast cancer susceptibility. Materials and Methods Eligible studies and data extraction PubMed and Embases databases were searched with the following terms: breast cancer/carcinoma, polymorphism/ variant, miR-146a/rs2910164, miR-196a2/rs11614913 or miR-499/rs3746444. The searched articles, published in English language updated to 31st December, 2012, were limited to human species, female sex and cancer subjects of adult patients (19+ years). All the titles and abstracts of searched articles were reviewed to exclude clearly irrelevant studies. The full texts of the remaining articles were read, and a manual search of the references from original studies was performed to identify additional articles of the same topic. All the case-control studies were studied according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) as a previous report [23]. The specific inclusion criteria as follows: (1) Case-control studies: cases are patients newly diagnosed with breast cancer, and the controls were subjects without breast cancer; (2) Odds ratios (ORs) with their 95 (...truncated)